Research news

In a study which suggests that genetic mutation was not necessarily the primary evolutionary
force producing morphological change in mammals, researchers report in the September
issue of Developmental Cell that the Drosophila Hmx gene partially rescued the development of the mouse inner ear, revealing that the
gene could direct the development of an organ it does not even possess.

When thinking of how new traits evolve, people have mainly focused upon mutations
in protein sequences said Thomas Lufkin, of the Genome Institute of Singapore, and senior author of the Developmental Cell study. "But, an equal possibility is that, instead of the gene sequence mutating,
the same gene can acquire new expression domains," Lufkin told us.

This possibility became apparent as Lufkin, lead author Weidong Wang, and their colleagues
began to study a family of homeobox genes termed Hmx. Drosophila has a single Hmx gene, termed DHmx, whose expression pattern suggests it is involved in the development of the Drosophila central nervous system (CNS). Two mouse Hmx genes, Hmx2 and Hmx3, are also involved in CNS development, but have additional roles in sensory organ
development. Thus, Lufkin and colleagues wondered what Hmx functions were conserved during evolution.

The researchers began by analyzing the phenotypes of Hmx2-/-, Hmx3-/- and Hmx2-/-/Hmx3-/- knockout mice, revealing Hmx2 and Hmx3 to have overlapping and distinct functions during development of the mouse inner
ear. They went on to create a mouse line with the Drosophila DHmx gene replacing Hmx3 and lacZ replacing Hmx2. As might be expected, DHmx rescued murine CNS development, an Hmx function that is conserved in Drosophila - but it also had effects on the development of the mouse inner ear.

"We didn't expect it to work as well as it did," said Lufkin, adding that these types
of experiments have been done in the past, but in many cases, the proteins failed
to rescue nonevolutionary conserved functions. "This demonstrates, at least in the
case of this one gene, that all the functional domains are still there, and implies
that it is through expression that [Hmx] has been evolutionary selected," Lufkin told us.

This addresses a very important evolutionary question, "the use of old genes for new
purposes," said Mario Capecchi, of the University of Utah, Salt Lake City, who was not involved in the Developmental Cell study. "It does not obviate mutations, but places the emphasis on the control of old
genes in new contexts, rather than mutations in their protein encoding regions," he
said.

"It's impressive work," said Jacqueline Deschamps, of the Netherlands Institute for
Developmental Biology, Utrecht, who was also not involved in the Developmental Cell study. Deschamps felt that the work by Lufkin and colleagues was nicely complemented
by a previous study, which suggested that the regulation of a Hox gene, HoxD, was coopted when vertebrates acquired novels structures such as limbs.

"These proteins regulate basic conserved processes, such as cell proliferation and
survival, so if by accident they are placed under the control of a new regulatory
region, and are suddenly expressed, say in the inner ear, they could play a major
role in the development there," Deschamps told us. And because Hmx and Hox genes are well-conserved master switches, it is reasonable to discover that the DHmx protein supports the development of an organ system that Drosophila does not possess, she said.

Overall, Lufkin feels that the acquisition of new contexts for old genes will become
a common theme in evolutionary developmental biology - often playfully referred to
as 'evodevo.' "As we go forward... we will tend to see that the idea of the cooption
of regulatory regions is just as viable a means of selection as the mutation of protein
coding sequences," he said.